Athletes engage in strenuous training to accomplish the goals of their sport. This strenuous training essentially amounts to trauma to the body, in that the human body interprets every strenuous work-out as a threat to its survival. It is known that muscle damage, caused by training, releases the catabolic hormone prostaglandin-E2. Training also causes the release of adrenocorticotropin (ACTH), which is a pituitary hormone. The presence of increased levels of ACTH increases the production of the catabolic hormone cortisol. Cortisol is also known as hydrocortisone, which is a glucocorticoid of the adrenal cortex that is a derivative of cortisone and is used in the treatment of rheumatoid arthritis. Thus, cortisol is a naturally occurring anti-inflammatory steroid. This catabolic hormone results in the release of amino acids from muscle tissue and prevents absorption of glucose. Cortisol, as a catabolic stress hormone, cannibalizes muscle tissue. High cortisol levels also result in the breakdown of connective tissue, lowered immunity and reduced muscle RNA synthesis. While cortisol may be a detriment to the athlete, scientists have conjectured that when the human body is stressed or traumatized, it triggers a "fight or flight" survival response. The biological design of cortisol is such that when a human is threatened, cortisol levels rise and mobilize the body for action by breaking down fat and muscle stores for emergency energy. Cortisol also reduces swelling in the event of injury. After the threat or trauma has subsided, cortisol levels return to normal. The cortisol-stress relationship is designed for intermittent physical threats and not the constant stimulation provided by today's aggressive athletes. Ongoing training results in cortisol levels that do not return to normal for extended periods of time and thereby result in the breakdown or loss of muscle tissue.
In order to reduce the catabolic effect of prolonged, intense training, a cortisol antagonist or blocker would be beneficial to the athlete. As used herein and in the claims the term "cortisol blocker" means any known chemical entity that, when administered to an animal, will retard or prevent the production of cortisol or inhibit or prevent the catabolic activity of cortisol against muscle tissue.
Monteleoni et al., European Journal of Clinical Pharmacology, pages 385-388 (1992) investigated the chronic administration of phosphatidylserine derived from brain cortex on the neuroendocrine responses to physical stress. The Monteleoni study found that phosphatidylserine derived from brain cortex administered orally at 800 mgs per day for 10 days prior to exercise, significantly reduced the ACTH and cortisol responses to physical exercise. A 400 mg per day dose was shown by Monteleoni to produce no effect on the cortisol response. Phosphaticlylserine is representative of a large class of neutral lipids. Phosphatidylserine is an essential component of biological membranes and occurs in the internal layer of the cell membrane.
In 1990, Monteleoni et al. reported in Neuroendocrinology, 1990; 52: pages 243-248, on the activity of brain cortex-derived phosphatidylserine on the neuroendocrine and neurovegetative responses to physical stress. In a double blind design, before starting the exercise, each human subject received intravenously the brain cortex derived phosphatidylserine or a placebo. Blood samples were collected before and after the exercise for plasma ACTH, cortisol and growth hormone. It was determined that physical stress induced an increase in ACTH, cortisol and growth hormone in the placebo group while the group receiving phosphatidylserine showed a reduced production of ACTH and cortisol.
.beta.-hydroxy-.beta.-methylbutyrate (HMB) is another compound known to increase lean-mass gains in weight trainers who consumed at least 3 grams per day. HMB is a leucine metabolite and it has been hypothesized from work in animal models that HMB decreases protein breakdown induced by resistance exercise, resulting in increased muscle mass and function.
U.S. Pat. No. 5,348,979 discloses a method of protein sparing, comprising orally or intravenously administering to a human .beta.-hydroxy-.beta.-methylbutyric acid (HMB). The '979 patent also teaches that the HMB can be in the free acid form, its mineral salts, esters or lactose derivatives. More specifically, the '979 patent discloses a method for improving the protein nutrition in elderly humans by administering HMB.
U.S. Pat. Nos. 5,360,613; 5,028,440 and 5,087,472 disclose and claim the administration of HMB to humans and meat producing domestic animals for treating elevated blood levels of low density lipoprotein cholesterol and total cholesterol, for increasing lean tissue development and for use as a feed additive. The teachings of U.S. Pat. Nos. 5,348,979; 5,360,613; 5,028,440 and 5,087,472 are herein incorporated by reference.
U.S. Pat. No. 4,981,687 discloses compositions and methods for achieving improved physiological response to exercise. More specifically, this patent teaches a beverage comprising water, sugar, electrolytes, glycerol and pyruvate; and its use to ameliorate the effects of physical exertion. The teachings of U.S. Pat. No. 4,981,687 are incorporated herein by reference.
U.S. Pat. No. 5,089,477 discloses the use of pyruvate in a liquid composition that is used to prevent weight loss in agricultural animals resulting from dehydration.
U.S. Pat. No. 5,147,650 and U.S. Pat. No. 5,238,684 discloses and claims a fluid composition comprising water, electrolytes, sugar, glycerol, lactate and pyruvate. The teachings of U.S. Pat. Nos. 5,147,650 and 5,238,684 are incorporated herein by reference.
U.S. Pat. No. 5,236,712 discloses and claims a beverage containing water, electrolytes, pyruvate and alanine in a concentration of from about 0.5% to about 10%. The teachings of U.S. Pat. No. 5,236,712 are incorporated herein by reference.
Dehydroepiandrosterone (DHEA) is a naturally occurring hormone produced by the adrenal gland. The level of serum DHEA decreases in humans from the age of about 25. Studies in humans have indicated that this hormone has the ability to increase muscle strength, add lean body mass, induce body fat loss, prolong endurance and increase IGF-1. Studies have shown that dosages of DHEA as high as 1.6 gm/day are safe and without side effects.
Nestler et al., in the Journal of Clinical Endocrinology and Metabolism, Vol. 66, No. 1 (pages 57-61) reported a DHEA study wherein five men were given a placebo and five men were given 1600 mg/day of DHEA for 28 days in a randomized double blind study. The DHEA group evidenced a mean percent body fat decrease of 31% with no change in weight. DHEA subjects also evidenced a fall in mean serum total cholesterol levels.
Morales et al., in the Journal of Clinical Endocrinology and Metabolism, Vol. 78, No. 6 (pages 1360-1367), reported a DHEA study wherein a randomized placebo-controlled cross-over trial of 50 mg per day DHEA administration for 6 months was conducted. The conclusion of this study was that restoration of DHEA in age advanced humans induced an increase in bioavailable IGF-1, which, with time, may result in an improvement in anabolic processes and physical/psychological well-being.
Conjugated linoleic acid (CLA) is found in cheese, lamb meat and bovine muscle tissue. Dosages of effective amounts of CLA are not practical from normal nutrition due to its low levels of concentration in regular foods. CLA is also known to have antioxidant properties like those of vitamin E and .beta.-carotene.
U.S. Pat. Nos. 5,430,066 and 5,428,072 to Cook et al. disclose and claim a method of enhancing weight gain and feed efficiency in an animal which comprises administration of a conjugated linoleic acid. More specifically, these patents relate to the enteral or parenteral administration of 9, 11-octadecadienoic acid; 10,12-octadecadienoic acid or the non-toxic salts thereof to mammals to increase the efficiency of feed conversion. These patents also claim a method of preventing weight loss, reduction in weight gain or anorexia in an animal caused by immune stimulation of the animal by endotoxin through the administration of conjugated linoleic acid, free linoleic acid, salts thereof and mixtures thereof. Even more specifically, the '066 patent discloses and claims a method for alleviating the adverse effects produced by interleukin-1 through the administration of CLA. The teachings of U.S. Pat. No. 5,430,066 and 5,428,072 are herein incorporated by reference.
A further example of known cortisol blockers, the compound known as ipriflavone (7-isoproxy-isoflavone) is submitted. Ipriflavone is presently used in dosages of about 600 mgs per day to treat women suffering from osteoporosis. Ipriflavone is known to have an anabolic effect on meat producing domestic animals. Human studies with an administration rate of 20 mg/kg/day of body weight,.evidenced an increase in body weight of about 5 pounds (2 kg) in four weeks without an increase in caloric intake. Ipriflavone is also known to increase athletic endurance, suppress the catabolic effect of cortisone and conserve nitrogen in skeletal muscle.
Creatine monohydrate is an additional cortisol blocker that, when combined with pyruvate, produces a synergistic effect in increasing the lean body mass of a mammal. The combination of pyruvate and creatine monohydrate also produces an increase in the athletic performance of the mammal by enhancing the energy level of the mammal.
Pregnenalone, a prohormone like DHEA, is a substance which the body utilizes to synthesize various hormones that regulate metabolism. Pregnenalone is known as a fat controlling agent and a lean tissue builder. Campbell reported in the Journal of Endocrinology, 94(2), 1982, pages 225-242, that exogenous pregnenalone increases the production of the anabolic steroid aldosterone while not increasing the production of the catabolic steroid corticosterone.
The present invention is based in part, upon the discovery that the use of pyruvate in enteral formulations, in combination with a cortisol blocker, such as phosphatidylserine, HMB, DHEA, CLA, creatine monohydrate, pregnenalone and the like, produces a synergistic effect in increasing the lean body mass or muscle tissue of a mammal consuming same. The synergistic compositions of the present invention will also have a very beneficial impact on treating the catabolic conditions associated with diseases such as AIDS and cancer.
As used herein and in the claims, the term "pyruvate" means any salt or ester of pyruvic acid. Pyruvic acid has the formula: ##STR1##
Pyruvic acid is a colorless liquid with an odor resembling that of acetic acid and has a melting point of 13.degree. C. Pyruvic acid is an intermediate in the breakdown of sugars to alcohol by yeast. The mineral salts of pyruvic acid, such as magnesium pyruvate, potassium pyruvate, calcium pyruvate or mixtures thereof are useful in the present invention. Sodium pyruvate is not especially preferred as it is known that sodium is associated with various negative medical conditions such as high blood pressure, water retention and heart disease. Further, certain athletes such as bodybuilders and gymnasts desire to present a defined visual image of their body which shows muscle definition and thus, the water retention properties of the sodium salt are not beneficial. Pyruvate precursors in the form of pyruvamides or pyruvyl-arnino acids are also useful in the present invention. Pyruvyl-glycine is representative of the useful pyruvyl-amino acids. Another pyruvate precursor is pyruvyl-creatine.
Pyruvate has a number of useful applications in medicine. Pyruvate has been described for retarding fatty deposits in livers (U.S. Pat. No. 4,158,057); for treating diabetes (U.S. Pat. No. 4,874,790); for retarding weight gain (U.S. Pat. Nos. 4,812,879, 4,548,937, and 4,351,835); to increase body protein concentrations in a mammal (U.S. Pat. No. 4,415,576); for treating cardiac patients to increase the cardiac output without accompanying increase in cardiac oxygen demand (U.S. Pat. No. 5,294,641); for extending athletic endurance (U.S. Pat. No. 4,3 15,835); for treating a hyperlipidemic animals (U.S. Pat. No. 5,134,162); for inhibiting growth and spread of malignancy and retarding DNA breaks (U.S. Pat. No. 5,612,374); and for inhibiting generation of free radicals (U.S. Pat. No. 5,480,409). All of these references are incorporated herein by reference.
Pyruvate in various forms has been proposed for enteral administration and for parenteral administration. Typically, pyruvates are available in the form of salts, for example, calcium pyruvate and magnesium pyruvate. U.S. Pat. Nos. 5,283,260 and 5,256,697 disclose uses for the pyruvyl-amino acids and methods for their production.
Pyruvate has been administered to mammals enterally or parenterally typically at superphysiological levels. The amount of pyruvate administered, generally ranges from 1 to 20% of the mammal's caloric intake. For enteral dosage, the pyruvate may be disbursed or dissolved in a beverage product or may be included in cookies, candies or other foods. Pyruvate may also be introduced as an aqueous solution parenterally.